We reviewed the ever increasing body of work on the impact of COMT (catechol-o-methyltransferase), a gene associated with risk for schizophrenia, on the efficiency of cognition, working memory, fluid intelligence and attentional control. There is a large body of work, in both humans and non-human primates, which shows the central role of the prefrontal cortex in information processing. We also know that dopamine regulates this information processing and that genetic factors influence the amount of dopamine in the brain. Here, we look at how the COMT polymorphism valine158methionine has helped to characterize various interacting aspects of complexity with relation to genes and cognition. We performed a critical examination of how COMT valine/methionine has been used to develop and validate behavioral and neurophysiological phenotypes. We look at how COMT has been used as a tool in delineating overlapping neural functional systems, and in exploring gene-gene and gene-environmental interactions. Lastly, how COMT is used in understanding gene affects on cognition are regulated by environmental, demographic and developmental influences. It has been well established that the amount of dopamine available in the prefrontal cortex is directly associated with the COMT val/met polymorphism. This affect is seen in differences in prefrontal physiology and information processing of COMT val/val carriers versus COMT met/met carriers. We have determined, by examination of COMTs role in schizophrenia, the COMT gene nicely illustrates the strategy of using genetic phenotype associations to examine neurobiological hypotheses regarding both healthy and impaired brain function. We will continue our work in this area, as there is still much to uncover about the association between genes and cognition and how to apply this knowledge in the field of behavioral medicine and treatments for schizophrenia.